<br>Nrf2 抗氧化信号的激活可减轻痛风关节炎疼痛和炎症,Biomedicine & Pharmacotherapy

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Nrf2 抗氧化信号的激活可减轻痛风关节炎疼痛和炎症
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2023-12-01 , DOI: 10.1016/j.biopha.2023.115957
Danyi Zeng ₁ , Chengyu Yin ₁ , Huina Wei ₁ , Yuanyuan Li ₁ , Yunqin Yang ₁ , Huimin Nie ₁ , Yushuang Pan ₁ , Ruoyao Xu ₁ , Yan Tai ₂ , Junying Du ₁ , Jinggen Liu ₁ , Ping Wang ₃ , Boyu Liu ₄ , Boyi Liu ₁

Affiliation

尿酸钠（MSU）晶体在关节内过度沉积会导致痛风性关节炎，引发剧烈疼痛并影响生活质量。氧化应激是导致痛风疼痛和炎症的关键机制。在这里，我们研究了激活 Nrf2（在调节内源性抗氧化反应中发挥重要作用）是否会通过促进关节组织中的抗氧化信号传导来减轻痛风关节炎。通过向小鼠右踝关节关节内注射MSU（500μg/踝）建立痛风关节炎模型。在模型建立前1小时和模型建立后5、23、47小时通过激活剂吡噻硫酮（50、100或150 mg/kg，腹腔注射）药理激活Nrf2，剂量依赖性地抑制模型小鼠的关节炎症、机械和热超敏反应。 Oltipraz (100 mg/kg) 可逆转步态障碍，而不改变运动活动，并减少踝关节中性粒细胞浸润。体外研究表明，吡噻硫酮 (25 μM) 可抑制小鼠巨噬细胞中 MSU 诱导的 ROS 产生，并改善 MSU 引起的线粒体生物能损伤。体内ROS成像结合生化测定证实了吡噻硫酮对模型小鼠的抗氧化作用。 Nrf2 激活抑制踝关节中促炎细胞因子的过度产生，并减弱支配后肢的 DRG 神经元中 TRPV1 通道的过度表达和增强。通过抑制 Nrf2 或在基因敲除小鼠中，吡噻硫酮的治疗作用被消除。这些结果表明，药理激活 Nrf2 可通过 Nrf2 依赖性抗氧化机制减轻痛风疼痛、步态障碍、炎症和外周敏化。靶向 Nrf2 可能代表痛风关节炎的一种新治疗选择。

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Activation of Nrf2 antioxidant signaling alleviates gout arthritis pain and inflammation

Excessive deposition of monosodium urate (MSU) crystal in the joint results in gout arthritis, which triggers severe pain and affects life quality. Oxidative stress is a pivotal mechanism that contributes to etiology of gout pain and inflammation. Here we investigated whether activating Nrf2, which plays important roles in regulating endogenous antioxidant response, would attenuate gout arthritis via promoting antioxidant signaling in joint tissues. Gout arthritis model was established by intra-articular injection of MSU (500 μg/ankle) into the right ankle joint of mouse. Pharmacologically activating Nrf2 by activator oltipraz (50, 100 or 150 mg/kg, intraperitoneal) at 1 h before and 5, 23, 47 h after model establishment dose-dependently inhibited joint inflammation, mechanical and heat hypersensitivities in model mice. Oltipraz (100 mg/kg) reversed gait impairments without altering locomotor activity and reduced neutrophil infiltrations in ankle joints. In vitro studies revealed oltipraz (25 μM) inhibited MSU-induced ROS production in mouse macrophages and improved mitochondrial bioenergetics impairments caused by MSU. In vivo ROS imaging combined with biochemical assays confirmed the antioxidant effects of oltipraz on model mice. Nrf2 activation inhibited pro-inflammatory cytokine overproduction in ankle joint and attenuated the overexpression and enhancement in TRPV1 channel in DRG neurons innervating hind limb. Therapeutic effects of oltipraz were abolished by inhibiting Nrf2 or in knockout mice. These results suggest pharmacologically activating Nrf2 alleviates gout pain, gait impairments, inflammation and peripheral sensitization via Nrf2-dependent antioxidant mechanism. Targeting Nrf2 may represent a novel treatment option for gout arthritis.

更新日期：2023-12-01

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